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Iron Metabolism in Ts65Dn mice, a Model of Down syndrome

Award Number: R15AG077421
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Iron Metabolism in Ts65Dn mice, a Model of Down syndrome - PROJECT SUMMARY/ABSTRACT Down syndrome (Ds) is a developmental disability that typically results from the triplication of chromosome 21 with an occurrence of 1 in 700 live births. Chromosome 21 triplication may alter normal gene expression and lead to intellectual disability, early onset Alzheimer’s disease, congenital heart disease, hematologic disorders, among other conditions. Dysregulation of iron homeostatic mechanisms may be an underlying factor in clinical outcomes associated with Ds. Iron is a trace element well-known for its involvement with physiological processes that include oxygen transport, inflammatory response, energy metabolism, and DNA synthesis. Iron homeostatic dysregulation in Ds could lead to compromised plasma iron levels and tissue iron accumulation that catalyzes the production of reactive oxygen radical species (ROS). Despite reports of iron status parameters in Ds there is a lack of clear and comprehensive understanding of iron homeostatic regulation among this population of individuals. The Ts65Dn mouse is an established model of Ds that may hold considerable value to study mechanistic factors that regulate iron homeostasis in Ds. The objective of this project is to delineate sex and age-related alterations in iron homeostatic regulation over the adult lifespan of Ts65Dn mice and to associate changes in iron regulation with tissue iron levels and oxidative stress. In these studies, tissues (brain, liver, and plasma) from Ts65Dn mice and wild-type (WT) colony controls at 3, 12, and 18 months of age will be studied to address two integrated Specific Aims: 1) Depict the iron homeostatic phenotype of Ts65Dn mice across the adult lifespan, and 2) Determine the impact of hypoxia exposure (10% inspired O2) on systemic and tissue iron homeostasis, hematologic profile, and tissue oxidative stress in Ts65Dn mice. The first aim of this proposal will establish the utility of the Ts65Dn mouse model to study iron status and iron homeostatic regulation in Ds. It is hypothesized that Ts65Dn mice will show greater inflammation that will promote an iron regulation response leading to lower plasma compartment iron and elevated iron in the storage compartment. Elevated tissue iron in Ts65Dn mice is postulated to associate with greater oxidative injury. The second aim will employ hypoxia exposure to alter iron homeostatic regulation of Ts65Dn and WT mice to test the hypothesis that hypoxia induced iron distribution shifts from storage to the plasma compartment will reduce Ts65Dn tissue iron toxicity and improve the hematologic profile. Furthermore, it is hypothesized that male mice will display greater iron status and oxidative stress than females, with Ts65Dn showing greater levels than WT controls. As iron metabolism dysregulation and tissue iron accumulation can become more prominent with aging, understanding iron metabolism in Ds is of utmost importance as life expectancy of this population has dramatically improved over the past several decades.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	000	1	9/17/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	000	1	1/18/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $465,330 )
2022	2022	UNIVERSITY OF HEALTH SCIENCES AND PHARMACY IN ST. LOUIS	1 PHARMACY PL	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	000	1	8/29/2022	NEW	$465,330
														Subtotal = $465,330

Grand Total All Awards = $465,330

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Iron Metabolism in Ts65Dn mice, a Model of Down syndrome

Award Number: R15AG077421

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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